Cloaked Caged Compounds: Chemical Probes for Two‐Photon Optoneurobiology

Abstract

Caged neurotransmitters, in combination with focused light beams, enable precise interrogation of neuronal function, even at the level of single synapses. However, most caged transmitters are, surprisingly, severe antagonists of ionotropic gamma-aminobutyric acid (GABA) receptors. By conjugation of a large, neutral dendrimer to a caged GABA probe we introduce a “cloaking” technology that effectively reduces such antagonism to very low levels. Such cloaked caged compounds will enable the study of the signaling of the inhibitory neurotransmitter GABA in its natural state using two-photon uncaging microscopy for the first time.

A red-shifted two-photon-only caging group for three-dimensional photorelease

“…Over the last decades photolabile protecting groups (PPGs) became a frequently used tool to regulate bioactive molecules 1 such as neurotransmitters, 2 – 5 hormones 6 , 7 and even macro-molecules like proteins 8 , 9 and oligonucleotides. 10 – 12 …”

Fulgazepam: A Fulgimide-Based Potentiator of GABAA Receptors

“…In addition, this ensures the application of quantitative amounts of either the open or the closed form. Thereby, a biological effect can clearly be assigned to one or the other conformation and enabling a photopharmacological profile corresponding to a pure modulator, without agonist or antagonist [40,41] or antagonist activies [42] which could interfere with endogenous neurotransmission. Synthetic investigations revealed the beneficial effects of an isopropyl group in the alpha bridge position of the fulgide, as the E-Z isomerization of the open isomer is suppressed due to steric hindrance and consequently only two distinct isomers are observed (Scheme 1).…”

Optimal Destabilization of DNA Double Strands by Single‐Nucleobase Caging

“…Ellis‐Davies et al. recently reported cloaking of caged GABA with dendrimers via click chemistry . Particularly with regard to in vivo applications, there is, however, still a considerable need for optimized oligonucleotide caging strategies.…”

“…[34] Ellis-Davies et al recently reportedc loaking of caged GABA with dendrimers via click chemistry. [35] Particularly with regard to in vivo applications, there is, however,s till ac onsiderable need for optimized oligonucleotide caging strategies. In this contribution, we investigate and maximize the destabilization of duplexesb yas ingle photolabile protecting group.…”